22 Chapter 2 2009). Fourth generation cephalosporins such as cefepime are an exception, as they are not hydrolysed by AmpC beta-lactamases. A second difference to most ESBLs is that commonly used beta-lactamase inhibitors such as clavulanic acid and tazobactam have very little or no effect on the AmpC activity. Cloxacillin and avibactam do have a good inhibitory effect on AmpC beta-lactamases. This characteristic of AmpC can be used in diagnostics (see paragraph Detection of plasmid AmpC ) (Jacoby 2009; J.A.J.W Kluytmans et al. 2021). Ever since the first studies on AmpC beta-lactamase in E. coli, this class of beta-lactamases has been found in a multitude of Enterobacterales and other Gramnegative bacteria over the years. For example, AmpC enzymes have been detected in Pseudomonas aeruginosa and Acinetobacter baumannii complex (Jacoby 2009). Although different AmpC beta-lactamases are very similar in enzyme structure, the genetic sequence differs per variant and species. The phenotype can also be very diverse. This is partly related to the phenomenon of induction and derepression of the AmpC beta-lactamase. AmpC production is related to cell wall degradation in gram-negative bacteria. As soon as more degradation products, such as 1,6-anhydromuropeptides, are released during the degradation of the cell wall, the expression of the ampC gene increases via a transcription regulator (AmpR). A second enzyme, called AmpD amidase, can initiate an alternative pathway in the cell wall degradation cycle that can inhibit ampC expression. Normally this phenomenon is balanced, but the administration of beta-lactam antibiotics increases the cell wall degradation and therefore causes an elevated ampC expression and subsequently the AmpC beta-lactamase production. This phenomenon is called induction, resulting in the typical resistant phenotype. Once the supply of cell wall degradation products decreases again, the expression of the ampC gene and the beta-lactamase production will return to the original level (Jacoby 2009). However, mutations can occur in the ampR or ampD gene, resulting in an adaptation in the enzyme structure. The cycle remains in a continuously increased status and in such cases, the beta-lactam resistance will be maintained without an increased supply of cell wall degradation products. This phenomenon is known as derepression and is mainly seen in Enterobacter spp, Klebsiella aerogenes and Citrobacter freundii (Jacoby 2009; Kohlmann, Bähr, and Gatermann 2018). This group of Enterobacterales is often referred to as “group II Enterobacterales”. When these mutants are selected out, for example under antibiotic pressure, the beta-lactam resistance remains constant and the microorganism can no longer be adequately treated with third-generation cephalosporins. In recent decades it has been discovered that ampC genes can also be encoded on plasmids (Jacoby 2009; Philippon, Arlet, and Jacoby 2002). Plasmids are circular
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